Project Summary/Abstract The complex architecture of cortical microcircuits is thought to comprise variations of canonical microcircuits that perform elemental computations. In the midst of specialized local computations, cortex also receives global input from a variety of long-range neuromodulatory centers. This proposal investigates the relationship between these two types of circuits. A recently identified cortical circuit motif is controlled by a class of interneurons defined by their expression of vasoactive intestinal polypeptide (VIP), which disinhibit pyramidal cells across four distinct cortical areas, thus defining a canonical cortical circuit. These VIP interneurons in the auditory cortex are recruited in response to reinforcement signals (reward and punishment), which are likely driven by neuromodulatory systems. Therefore the dual objectives of this proposal are to determine both the generality of VIP recruitment by reinforcement signals and the circuit mechanisms responsible for this activity. First we will evaluate the cortex-wide generality of VIP interneuron recruitment by reinforcers using a combination of sophisticated techniques for neuron identification and evaluation of their activity. Second, we will identify which inputs drive reinforcement responses in VIP neurons. We will map all common regions across the brain that provide inputs to cortical VIP neurons, with a focus on the cholinergic and serotonergic neuromodulatory systems and determine the pathway(s) causally responsible. Finally, we will determine how different subtypes of VIP neurons are recruited and driven. Completion of these aims should reveal fundamental principles of how the VIP- controlled cortical microcircuit functions cortex-wide and serves as a conduit for fast neuromodulatory control.